Choosing Treatment: With What

Once you have made the decision to start treatment, the next challenge is choosing the drugs in the combination. Despite any drug-company-generated hype you may have read, there is no single best combination of drugs and no best starting combination. We can all agree that an effective combination is one that will drop your viral load as low as possible and raise your CD4+ count as high as possible. And we could probably get most people to agree that, for you, the best combination is one that meets those goals but also works for you and your lifestyle. That's where our consensus will most likely end.

The problem is that there is no clear-cut, long-term data that proves that starting with X, Y and Z drugs gives you: (a) the best chance for initial success, and (b) lots of remaining treatment choices down the line. And both are hugely important. Since most people have their best response to their first regimen, it is obviously important to choose one that has proven potency, side effects you can tolerate, and a dosing schedule that you can really, truly adhere to. This will give you the best possible chance for getting the immune-restoring benefits that any first regimen should aim for.

In addition, you want to strongly consider whether this first combination will leave you with many future options. Sadly, you're not likely to be able to continue with the same regimen forever. Eventually, there is a possibility that the drugs may fail (due to resistance or other problems) or that long-term side effects will become too difficult. Each choice you make with your first regimen will affect what treatment choices will be available to you when this initial combination fails. This concern means that you need to strongly consider the sequencing of your drug combinations.

So, if you haven't already started treatment, before you even start Combo #1, consider how it will affect your possible downstream treatment choices. Write down a plan that considers which options will be available to you for Combo #2 when #1 goes by the wayside, and for Combos 3, 4, 5 and so on -- if and when you need them. If you're already on HAART and haven't done this yet, start now to plan as carefully as possible. Pick up that pen and paper and consider where you've been and what is still available to you, based on your medication history.

Yes, there may be future options that are not even known yet, but you need to make knowledgeable decisions now, based on everything currently known and available. Later, you can revise this plan as more is known and future drugs are added to the list of possibilities. For now, your choices are fundamentally these:

For details on the ways in which the different drugs work, see "Viral Life Cycle" section; for their many names, see "Appendix A, Antiretroviral Drugs."

A Protease Inhibitor-Based Regimen

Most commonly, this will mean a combination of one protease inhibitor (PI) with two drugs from the earliest class of anti-HIV drugs, the nucleoside analogue reverse transcriptase inhibitors (nukes or NRTIs). Other possibilities that some have used successfully include the use of two PIs with either a single nuke or a single non-nuke (NNRTI), or two PIs and two nukes.

The one-PI/two-nuke combination is the oldest version of HAART, and thus the one for which we have the best long-term data. Prior to the development of PIs most people were already on two nukes. When this new class became available (and it became clear that PIs would lead to quick development of drug resistance when used alone), the PI was just added to what was already being taken. This approach has a long track record of successful use, and its power as a treatment combination is well proven. However, currently available PIs have many possible side effects.

If you find the prospect of certain side effects particularly troubling or you have difficulty with scheduling and food issues or large numbers of pills, you might want to consider one of the other possible regimens. Alternately, you can also consider PI-boosting. This involves the use of ritonavir (Norvir) given in low doses (usually 100-200 mg) with another protease inhibitor in order to slow down the breakdown of the other PI in the liver, and thus increase its level in the bloodstream to make it more effective. Ritonavir has this effect because it inhibits certain liver enzymes. This ritonavir/2nd PI combo often reduces dosing frequency and the total number of pills that need to be taken, and sometimes eliminates certain food requirements, making PI-based regimens more user-friendly. However, it does not usually eliminate side effects.

A Protease-Sparing Regimen

The most common of these regimens uses a combination of a non-nuke with two nukes (just as in the PI-based combination, but substituting a non-nuke for the PI). When protease-sparing regimens have been compared to PI-based regimens in clinical trials, they have generally appeared to be similar in their effectiveness. These regimens may require fewer pills. And they will, indeed, eliminate some of the troubling PI-caused side effects, but use of non-nukes can cause a different set of side effects in some people.

A Two-Class-Sparing All-Nukes Regimen

This approach uses all nukes all the time, most commonly Glaxo's Trizivir (AZT/3TC/abacavir). This only requires a single pill taken twice daily, so it makes sticking to your treatment schedule easier. And it will eliminate the side effects that are only likely with PIs or non-nukes; but, of course, nukes have side effects of their own. However, current guidelines do not recommend this approach for initial therapy.

The Kitchen-Sink Regimen

Seldom used for initial treatment unless the patient absolutely demands it, but more common for those seeking rescue or salvage therapy when multiple earlier regimens have failed, this involves the use of drugs from all three classes -- often one or two PIs combined with one or two nukes and a non-nuke. The obvious idea is high potency combined with hitting the virus in three different ways, with the hope that this will make it much more difficult for the virus to effectively mutate to become drug resistant. But even if this approach worked perfectly in these ways, it would have the strong disadvantage of a much higher likelihood of drug toxicity and side effects -- not to mention all those pills.

And last, but definitely not least, there is the possibility of using up all three currently available classes of drugs. If resistance to such an approach develops, there could be no place left to look for another combination until whole new classes of drugs become readily available or at least until drugs within the current classes that are not cross-resistant are developed.

A Kinder, Simpler Regimen: Once-Daily Therapy

The complexity of most of the earlier generation HAART regimens -- especially the requirement to take large numbers of pills several times per day and schedule them perfectly, often with stringent dietary restrictions -- has led to increasing interest in the possibility of simplifying regimens. There are now several approaches that would allow all the medications to be taken in just one or two doses daily. Both research and many reports from clinicians seem to indicate that such approaches greatly increase the likelihood of adherence, and thus of long-term drug effectiveness. And, for obvious reasons, most PHAs greatly prefer these simplified regimens.

However, there are significant potential drawbacks that should be considered. If drugs are only being taken once a day, skipping even one dose means that for quite a lengthy period there will be suboptimal (inadequate) amounts of the drug in the bloodstream, increasing the chance of developing drug resistance. Overall, this means that although adherence to such drugs will be easier -- you only have to remember to take them at one particular time every day -- you will need to be absolutely consistent in always taking that one dose. In addition, if the goal is having only one time every day when drugs are taken, your options will be limited to drugs that can be taken at the same time (some drugs have interactions that require them to be taken at different times) and with the same food requirements (with food or on an empty stomach). This will somewhat limit your treatment possibilities.

Below is a list of several drugs that are options for once-daily therapy; note that not all of these drugs may be covered in your province or territory:

• efavirenz (Sustiva) -- a non-nuke which is taken either as three 200 mg tablets, or one 600 mg capsule, usually at bedtime; and

• a delayed-release formulation of ddI (didanosine, Videx EC) -- a nuke which is taken as one 400 mg capsule, either one hour before or two hours after a meal to improve absorption.

• 3TC (lamivudine, Epivir) -- a nuke now approved for dosing at 150 mg twice daily or 300 mg once per day;

• ABC (abacavir, Ziagen) -- a nuke currently approved for dosing at 300 mg twice daily; researchers are testing 600 mg once daily; and

• tenofovir (Viread) -- a nucleotide reverse transcriptase inhibitor taken in a dose of one 300-mg tablet, once daily, with food;

• atazanavir (BMS-232632, Reyataz) -- a protease inhibitor taken once daily with food; and

• FTC (emtricitabine, Emtriva) -- a nuke taken in a dosage of one 200-mg capsule, once daily.

Any of these once-daily drugs must, of course, still be given with other drugs to create an effective combination. Thus, in order to create a truly once-daily regimen, it will be necessary to choose workable combinations from these once-daily candidates.

NOTE: For more information on specific HIV drugs, check out CATIE's Fact Sheets at www.catie.ca/facts.nsf or by calling 1.800.263.1638 [if you're in Canada].